scholarly journals Systemic Glycosaminoglycan Clearance by HARE/Stabilin-2 Activates Intracellular Signaling

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2366
Author(s):  
Paul H. Weigel
Keyword(s):  
Intracellular Signaling ◽  
Dermatan Sulfate ◽  
Specific Binding ◽  
Target Surface ◽  
Cell Types ◽  
Scavenger Receptors ◽  
Extracellular Signal Regulated Kinase ◽  
Chondroitin Sulfates ◽  
Extracellular Signal ◽  
Receptor Purification

Scavenger receptors perform essential functions, critical to maintaining mammalian physiologic homeostasis by continuously clearing vast numbers of biomolecules from blood, interstitial fluid and lymph. Stabilin-2 (Stab2) and the Hyaluronic Acid Receptor for Endocytosis (HARE), a proteolytic isoform of Stab2, are important scavenger receptors responsible for the specific binding and internalization (leading to degradation) of 22 discrete molecules, macromolecular complexes and cell types. One-third of these ligands are glycosaminoglycans (GAGs). Full-length Stab2, but not HARE, mediates efficient phagocytosis of apoptotic cells and bacteria via binding to target surface ligands. HARE, the C-terminal half of Stab2, mediates endocytosis of all the known soluble ligands. HA was the first ligand identified, in 1981, prior to receptor purification or cloning. Seven other GAG ligands were subsequently identified: heparin, dermatan sulfate, chondroitin and chondroitin sulfates A, C, D and E. Synthetic dextran sulfate is also a GAG mimic and ligand. HARE signaling during HA endocytosis was first discovered in 2008, and we now know that activation of HARE/Stab2 signaling is stimulated by receptor-mediated endocytosis or phagocytosis of many, but not all, of its ligands. This review focuses on the HARE-mediated GAG activation of intracellular signaling, particularly the Extracellular Signal-Regulated Kinase 1/2 pathway.

scholarly journals Pituitary Adenylate Cyclase-Activating Polypeptide Protects Glomerular Podocytes from Inflammatory Injuries

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Kenichi Sakamoto ◽  
Kyoko Kuno ◽  
Minoru Takemoto ◽  
Peng He ◽  
Takahiro Ishikawa ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Treatment Options ◽  
Cell Types ◽  
Specific Cell ◽  
Monocyte Chemoattractant Protein 1 ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Pituitary Adenylate Cyclase ◽  
End Stage ◽  
Anti Inflammation

Diabetic nephropathy (DN) is a leading cause of end-stage kidney disease; however, there are few treatment options. Inflammation plays a crucial role in the initiation and/or progression of DN. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide, which was originally isolated from the ovine hypothalamus and reportedly has diverse biological functions. It has been reported that PACAP has renoprotective effects in different models of kidney pathology. However, the specific cell types within the kidney that are protected by PACAP have not yet been reported. In this study, we localized VPAC1, one of the PACAP receptors, to glomerular podocytes, which also reportedly has crucial roles not only in glomerular physiology but also in pathology. PACAP was effective in the downregulation of proinflammatory cytokines, such as monocyte chemoattractant protein-1 (MCP-1) and interleukin-6, which had been induced by the activation of toll-like receptor (TLR) with lipopolysaccharide. PACAP also had downregulated the expression of MCP-1 through the protein kinase A signaling pathway; this led to the attenuation of the activation of extracellular signal-regulated kinase and nuclear factor-kappa B signaling. Our results suggested that PACAP could be a possible treatment option for DN through the use of anti-inflammation effects on glomerular podocytes.

Signaling through the extracellular signal-regulated kinase 1/2 cascade in cardiac myocytes

2004 ◽  
Vol 82 (6) ◽  
pp. 603-609 ◽  
Author(s):  
Angela Clerk ◽  
Peter H Sugden
Keyword(s):  
Cardiac Myocytes ◽  
Intracellular Signaling ◽  
Regulation Of Transcription ◽  
Signal Integration ◽  
Extracellular Signal Regulated Kinase ◽  
Kinase C ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Protein Kinase C Isoforms ◽  
Activate Protein Kinase

The extracellular signal-regulated kinases 1/2 (ERK1/2) are particularly implicated in the growth response of cardiac myocytes. In these cells, the ERK1/2 pathway is potently activated by Gq protein-coupled receptor agonists (such as endothelin-1 or α-adrenergic agonists), which activate protein kinase C isoforms. Here, we review the mechanisms associated with the activation of the ERK1/2 pathway by these agonists with particular emphasis on signal integration into the pathway. Signaling to the nucleus and the regulation of transcription factor activity associated with ERK1/2 activation in cardiac myocytes are also discussed.Key words: mitogen-activated protein kinases, cardiac myocytes, intracellular signaling.

scholarly journals Phosphorylation of the Carboxyl-Terminal Transactivation Domain of c-Fos by Extracellular Signal-Regulated Kinase Mediates the Transcriptional Activation of AP-1 and Cellular Transformation Induced by Platelet-Derived Growth Factor

2003 ◽  
Vol 23 (19) ◽  
pp. 7030-7043 ◽  
Author(s):  
Paula Monje ◽  
Maria Julia Marinissen ◽  
J. Silvio Gutkind
Keyword(s):  
Transcription Factors ◽  
Growth Factor ◽  
Cell Growth ◽  
Intracellular Signaling ◽  
Cellular Transformation ◽  
Platelet Derived Growth Factor ◽  
Transactivation Domain ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Carboxyl Terminal

ABSTRACT Polypeptide growth factors, such as platelet-derived growth factor (PDGF), promote the reinitiation of DNA synthesis and cell growth through multiple intracellular signaling pathways that converge in the nucleus to regulate the activity of transcription factors, thereby controlling the expression of growth-promoting genes. Among them, the AP-1 (activating protein-1) family of transcription factors, including c-Fos and c-Jun family members, plays a key role, as AP-1 activity is potently activated by PDGF and is required to stimulate cell proliferation. However, the nature of the pathways connecting PDGF receptors to AP-1 is still poorly defined. In this study, we show that PDGF regulates AP-1 by stimulating the expression and function of c-Fos through extracellular signal-regulated kinase (ERK). The latter involves the direct phosphorylation by ERK of multiple residues in the carboxyl-terminal transactivation domain of c-Fos, which results in its increased transcriptional activity. Interestingly, the phosphorylation of c-Fos by ERK was required for the ability of PDGF and serum to stimulate the activity of c-Fos as well as AP-1-dependent transcription. Furthermore, we provide evidence that the ERK-dependent activation of c-Fos is an integral component of the mitogenic pathway by which PDGF regulates normal and aberrant cell growth.

scholarly journals p38α Mitogen-activated Protein Kinase Sensitizes Cells to Apoptosis Induced by Different Stimuli

2004 ◽  
Vol 15 (2) ◽  
pp. 922-933 ◽  
Author(s):  
Almudena Porras ◽  
Susana Zuluaga ◽  
Emma Black ◽  
Amparo Valladares ◽  
Alberto M. Alvarez ◽  
...  
Keyword(s):  
Map Kinase ◽  
Cell Types ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Survival Pathways ◽  
Proapoptotic Protein ◽  
Extracellular Signal ◽  
Survival Pathway ◽  
Mitogen Activated Protein

p38α mitogen-activated protein (MAP) kinase is a broadly expressed signaling molecule that participates in the regulation of cellular responses to stress as well as in the control of proliferation and survival of many cell types. We have used cell lines derived from p38α knockout mice to study the role of this signaling pathway in the regulation of apoptosis. Here, we show that cardiomyocytes and fibroblasts lacking p38α are more resistant to apoptosis induced by different stimuli. The reduced apoptosis of p38α-deficient cells correlates with decreased expression of the mitochondrial proapoptotic protein Bax and the apoptosis-inducing receptor Fas/CD-95. Cells lacking p38α also have increased extracellular signal-regulated kinase (ERKs) MAP kinase activity, and the up-regulation of this survival pathway seems to be at least partially responsible for the reduced levels of apoptosis in the absence of p38α. Phosphorylation of the transcription factor STAT3 on Ser-727, mediated by the extracellular signal-regulated kinase MAP kinase pathway, may contribute to the decrease in both Bax and Fas expression in p38α-/- cells. Thus, p38α seems to sensitize cells to apoptosis via both up-regulation of proapoptotic proteins and down-regulation of survival pathways.

Tuning the volume of the immune response: strength and persistence of stimulation determine migration and cytokine secretion of dendritic cells

Blood ◽  
2004 ◽  
Vol 104 (4) ◽  
pp. 1066-1074 ◽  
Author(s):  
Thomas Luft ◽  
Eugene Maraskovsky ◽  
Max Schnurr ◽  
Katja Knebel ◽  
Michael Kirsch ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Intracellular Signaling ◽  
Cd40 Ligand ◽  
Response Strength ◽  
Cytokine Secretion ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Cd40 Activation ◽  
Novel Concept

AbstractMigration to lymph nodes and secretion of cytokines are critical functions of mature dendritic cells (DCs); however, these 2 functions are not necessarily linked. This is the first report showing that quantitative differences in identical signaling pathways determine DC migration and cytokine secretion. Using different polymerized forms of CD40 ligand, we demonstrate that the strength and persistence of CD40 signaling can induce either function. Induction of monocyte-derived DC (MoDC) migration required a weak and transient CD40 signal, whereas strong and persistent CD40 signaling blocked migration and biased toward cytokine secretion. In contrast to MoDCs, CD40 activation of CD1c+ peripheral blood DCs (PBDCs) induced a nonpersistent, intracellular signaling profile resulting in migratory-type DCs unable to secrete interleukin-12p70 (IL-12p70). Extracellular signal-regulated kinase 1/2 (ERK1/2) and p38K activation synergistically mediated cytokine secretion, whereas migration was enhanced by p38K activation but reduced by persistent ERK1/2 activity. This model of signal strength and persistence also applied when stimulating DCs with intact microbes. Thus, a novel concept emerges in which the type of immune response induced by DCs is tuned by the strength and persistence of DC activating signals.

Intracellular signaling specificity in response to uniaxial vs. multiaxial stretch: implications for mechanotransduction

2005 ◽  
Vol 288 (1) ◽  
pp. C185-C194 ◽  
Author(s):  
Troy A. Hornberger ◽  
Dustin D. Armstrong ◽  
Timothy J. Koh ◽  
Thomas J. Burkholder ◽  
Karyn A. Esser
Keyword(s):  
Intracellular Signaling ◽  
Growth Factor Receptor ◽  
Mechanical Stretch ◽  
Mechanical Stimuli ◽  
Paracrine Factors ◽  
Signaling Specificity ◽  
Akt Phosphorylation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Ribosomal S6 Kinase

Several lines of evidence suggest that muscle cells can distinguish between specific mechanical stimuli. To test this concept, we subjected C2C12 myotubes to cyclic uniaxial or multiaxial stretch. Both types of stretch induced an increase in extracellular signal-regulated kinase (ERK) and protein kinase B (PKB/Akt) phosphorylation, but only multiaxial stretch induced ribosomal S6 kinase (p70S6k) phosphorylation. Further results demonstrated that the signaling events specific to multiaxial stretch (p70S6k phosphorylation) were elicited by forces delivered through the elastic culture membrane and were not due to greater surface area deformations or localized regions of large tensile strain. Experiments performed using medium that was conditioned by multiaxial stretched myotubes indicated that a release of paracrine factors was not sufficient for the induction of signaling to p70S6k. Furthermore, incubation with gadolinium(III) chloride (500 μM), genistein (250 μM), PD-98059 (250 μM), bisindolylmaleimide I (20 μM), or LY-294002 (100 μM ) did not block the multiaxial stretch-induced signaling to p70S6k. However, disrupting the actin cytoskeleton with cytochalasin D did block the multiaxial signaling to p70S6k, with no effect on signaling to PKB/Akt. These results demonstrate that specific types of mechanical stretch activate distinct signaling pathways, and we propose that this occurs through direct mechanosensory-mechanotransduction mechanisms and not through previously defined growth factor/receptor binding pathways.

scholarly journals Detection of receptors for sulfated polysaccharides in human placenta by biotinylated probes.

1988 ◽  
Vol 36 (9) ◽  
pp. 1097-1102 ◽  
Author(s):  
P L Debbage ◽  
W Lange ◽  
T Hellmann ◽  
H J Gabius
Keyword(s):  
Developmental Stage ◽  
Human Placenta ◽  
Binding Sites ◽  
Dermatan Sulfate ◽  
Specific Binding ◽  
Cell Types ◽  
Sulfated Polysaccharides ◽  
Stage Of Development ◽  
Different Cell Types ◽  
Biotinylated Probes

Histochemical detection of binding sites for sulfated polysaccharides believed to be important mediators within recognitive interactions was carried out by application of biotinylated probes such as heparin, native and desulfated fucoidan, dermatan sulfate, and two types of carrageenans. The probes were derivatized by mild cyanogen bromide activation and subsequent aminoalkylation to allow incorporation of biotin, inserted with an epsilon-aminocaproic acid spacer to reduce charge-related and steric impediments. Specific labeling could be detected in different cell types of human placenta, dependent on the developmental stage. Sulfated polysaccharides bound predominantly to leucocytes in full-term placenta, whereas demonstration of specific binding sites in decidua, syncytiotrophoblasts, and cytotrophoblasts was restricted primarily to heparin and, less intensely, fucoidan, although not desulfated fucoidan. Heparin binding in the placenta after 8 weeks of gestation was reduced for epithelia that, at this stage of development, revealed carrageenan binding sites. Fucoidan binding was at this developmental stage measurable only for leucocytes. These results provide definite histochemical evidence for the presence and developmental regulation of expression of receptors for sulfated polysaccharides in different cell types of human placenta.

scholarly journals Up-Regulation of Interleukin-8 by Novel Small Cytoplasmic Molecules of Nontypeable Haemophilus influenzae via p38 and Extracellular Signal-Regulated Kinase Pathways

2003 ◽  
Vol 71 (10) ◽  
pp. 5523-5530 ◽  
Author(s):  
Beinan Wang ◽  
P. Patrick Cleary ◽  
Haidong Xu ◽  
Jian-Dong Li
Keyword(s):  
Protein Kinase ◽  
Haemophilus Influenzae ◽  
Intracellular Signaling ◽  
Interleukin 8 ◽  
Mitogen Activated Protein Kinase ◽  
Akt Pathway ◽  
Chronic Obstructive ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT Nontypeable Haemophilus influenzae (NTHI) is an important etiological agent of otitis media (OM) and of exacerbated chronic obstructive pulmonary diseases (COPD). Inflammation is a hallmark of both diseases. Interleukin-8 (IL-8), one of the important inflammatory mediators, is induced by NTHI and may play a significant role in the pathogenesis of these diseases. Our studies demonstrated that a soluble cytoplasmic fraction (SCF) from NTHI induced much greater IL-8 expression by human epithelial cells than did NTHI lipooligosaccharides and envelope proteins. The IL-8-inducing activity was associated with molecules of ≤3 kDa from SCF and was peptidase and lipase sensitive, suggesting that small lipopeptides are responsible for the strong IL-8 induction. Moreover, multiple intracellular signaling pathways were activated in response to cytoplasmic molecules. The results indicated that the p38 mitogen-activated protein kinase (MAPK) and Src-dependent Raf-1-Mek1/2-extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) pathways are required for NTHI-induced IL-8 production. In contrast, the phosphatidylinositol 3-kinase (PI3K)-Akt pathway did not affect IL-8 expression, although this pathway was concomitantly activated upon exposure to NTHI SCF. The PI3K-Akt pathway was also directly activated by IL-8 and significantly inhibited by an antagonist of IL-8 receptors during NTHI stimulation. These results indicated that the PI3K-Akt pathway is activated in response to IL-8 that is induced by NTHI and may lead to other important epithelial cell responses. This work provides insight into essential molecular and cellular events that may impact on the pathogenesis of OM and COPD and identifies rational targets for anti-inflammatory intervention.

scholarly journals Differential Induction of Nuclear Factor-κB and Activator Protein-1 Activity after CD40 Ligation Is Associated with Primary Human Hepatocyte Apoptosis or Intrahepatic Endothelial Cell Proliferation

2003 ◽  
Vol 14 (4) ◽  
pp. 1334-1345 ◽  
Author(s):  
Jalal Ahmed Choudhury ◽  
Clare L. Russell ◽  
Satinder Randhawa ◽  
Lawrence S. Young ◽  
David H. Adams ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Types ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Cd40 Ligation ◽  
Differential Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Induction Of Apoptosis

CD40, a tumor necrosis factor receptor superfamily member, is up-regulated on intraheptatic endothelial cells (IHEC) and epithelial cells during inflammatory liver disease, and there is evidence that the functional outcome of CD40 ligation differs between cell types. Ligation of CD40 on cholangiocytes or hepatocytes results in induction of Fas-mediated apoptosis, whereas ligation of IHEC CD40 leads to enhanced chemokine secretion and adhesion molecule expression. We now report that differential activation of two transcription factors, nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), in primary human hepatocytes or IHEC, is associated with and may explain, in part, the different responses of these cell types to CD40 ligation. CD40 ligation induced a rise in NF-κB activity in hepatocytes ,which peaked at 2 h and returned to baseline by 24 h; however, IHEC CD40 ligation resulted in a sustained up-regulation of NF-κB (>24 h). In hepatocytes, CD40 ligation led to sustained up-regulation of AP-1 activity >24 h associated with increased protein levels of RelA (p65), c-Jun, and c-Fos, whereas no induction of AP-1 activity was observed in IHECs. Analysis of mitogen-activated protein kinase phosphorylation (phospho-extracellular signal-regulated kinase 1/2 and phospho-c-Jun NH2-terminal kinase 1/2) and expression of inhibitor κBα were entirely consistent, and thus confirmed the profiles of NF-κB and AP-1 signaling and the effects of the selective inhibitors assessed using electrophoretic mobility shift assay or Western immunoblotting. CD40 ligation resulted in induction of apoptosis in hepatocytes after 24 h, but on IHECs, CD40 ligation resulted in proliferation. Inhibition of (CD40-mediated) NF-κB activation prevented IHEC proliferation and led to induction of apoptosis. Selective extracellular signal-regulated kinase and c-Jun NH2-terminal kinase inhibitors reduced levels of apoptosis in (CD40-stimulated) hepatocytes by ∼50%. We conclude that differential activation of these two transcription factors in response to CD40 ligation is associated with differences in cell fate. Transient activation of NF-κB and sustained AP-1 activation is associated with apoptosis in hepatocytes, whereas prolonged NF-κB activation and a lack of AP-1 activation in IHECs result in proliferation.

Phosphatase-Mediated Intracellular Signaling Contributes to Neuroprotection by Flavonoids of Iris tenuifolia

2014 ◽  
Vol 42 (01) ◽  
pp. 119-130 ◽  
Author(s):  
Aldarmaa Jalsrai ◽  
Tadahiro Numakawa ◽  
Yoshiko Ooshima ◽  
Naoki Adachi ◽  
Hiroshi Kunugi
Keyword(s):  
Cortical Neurons ◽  
Intracellular Signaling ◽  
Sh2 Domain ◽  
Promoting Effect ◽  
Extracellular Signal Regulated Kinase ◽  
Src Homology 2 ◽  
Extracellular Signal ◽  
Cultured Cortical Neurons ◽  
Src Homology ◽  
Phosphoinositide 3 Kinase

A variety of flavonoids are suggested to be useful for the treatment of brain-related disorders, including dementia and depression. An investigation on the characteristics of the extracted compounds of Iris tenuifolia Pall. (IT) is of much interest, as this plant has been used as a traditional medicine. In the present study, we examined the effect of total flavonoids obtained from IT on cultured cortical neurons under oxidative-stress and found that pretreatment with IT flavonoids significantly inhibited H 2 O 2-induced cell death in cortical neurons. Such a survival-promoting effect by IT flavonoids was partially blocked by inhibitors for extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase/Akt (PI3K/Akt) cascades, both of which are known as survival-promoting signaling molecules. Furthermore, the phosphorylation of Src homology-2 (SH2) domain-containing phosphatase2 (Shp2) was induced by IT flavonoids, and the protective effect of IT flavonoids was abolished by NSC87877, an inhibitor for Shp2, suggesting the involvement of Shp2-mediated intracellular signaling in flavonoid-dependent neuroprotection.

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